Oncology
DA-3502
Unmet needs
DA-3502 is a bispecific antibody-drug conjugate (bsADC) designed to independently recognize CLDN18.2 and HER2. It is being developed to address target-expression heterogeneity in gastric cancer and to mitigate the limitations of single-target treatment paradigms, with the aim of broadening therapeutic options for tumors expressing CLDN18.2 and/or HER2.
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High Disease Burden and Heterogeneous Target Expression
Gastric cancer remains a major global health burden, with particularly high incidence and mortality in East Asia. Although biomarker-guided therapies targeting HER2 and CLDN18.2 have expanded treatment options, intratumoral and interlesional heterogeneity in target expression may limit the coverage of diverse tumor-cell subpopulations by single-target therapies. -
Applicability and Safety Constraints of Single-Target Therapies
Biomarker-driven therapies, including trastuzumab deruxtecan (T-DXd) for HER2-positive cancer and zolbetuximab for CLDN18.2-positive cancer, have expanded the treatment landscape. However, eligibility is guided by biomarker-expression thresholds, and spatial or temporal heterogeneity, together with antigen down-regulation or loss during treatment, may contribute to variable therapeutic benefit. Treatment-related risks, including interstitial lung disease (ILD)/pneumonitis with HER2-targeted ADC and nausea/vomiting with CLDN18.2 targeted therapy, also require consideration in long-term treatment. -
Broader Tumor-Cell Coverage through Dual Targeting
DA-3502 is designed to independently recognize CLDN18.2 and HER2, enabling coverage across CLDN18.2-positive, HER2-positive, and dual-positive tumor-cell subpopulations. This approach may complement single-target therapies in heterogeneous tumors, reduce the risk of tumor escape associated with target down-regulation or loss, and potentially extend therapeutic applicability to patient populations insufficiently benefiting from existing single-target therapies.
MoA (Mechanism of Action)
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Dual Target Recognition of CLDN18.2 and HER2
DA-3502 is a bispecific ADC assembled in an IgG-like format using Dong-A ST’s enhanced knob-into-hole (eKiH) platform, which enables efficient antibody heterodimerization while preserving an IgG-like architecture. It is designed to recognize CLDN18.2 and HER2 independently, thereby providing broad coverage of CLDN18.2-positive, HER2-positive, or dual-positive tumor cells. -
Target-Mediated Internalization and Payload Release
Upon binding to CLDN18.2 or HER2 on the tumor-cell surface, the ADC-antigen complex is expected to undergo endocytosis and lysosomal trafficking. Subsequent linker processing releases the cytotoxic payload intracellularly, thereby mediating tumor-cell death. Where the released payload is membrane permeable, it may also exert a bystander effect on neighboring tumor cells. -
Potential to Address Target-Expression Heterogeneity
DA-3502 is designed to address the inherent reliance of single-target ADCs on a single antigen by independently targeting CLDN18.2 and HER2. If expression of one target is low or lost, the alternate target may maintain tumor-cell recognition, providing a potentially more robust strategy for addressing target-expression heterogeneity and dynamic antigen-expression changes in gastric cancer.
